1-aryl-4-imino-1, 2, 3, 4-tetrahydroquinazolines



United States Patent 3,403,152 1-ARYL-4-IMINO-1,2,3,4-TETRAHYDRO-QUINAZOLINES Herbert Morton Blatter, Springfield, N.J., assignor to CibaCorporation, New York, N.Y., a corporation of Delaware N0 Drawing.Continuation-impart of application Ser. No. I 509,613, Nov. 24, 1965.This application Mar. 20, 1967, Ser. No. 624,210

Claims. (Cl. 260256.4)

ABSTRACT OF THE DISCLOSURE Ph=a 1,2-phenylene Rf=aromatic radical R'=aliphatic or aromatic radical R =H or aliphatic radical R =H, aliphaticor aromatic radical N-oxides, quaternaries and salts thereof, eg the4-n-propyl imino 1(4-fluoro-phenyl)-2-phenyl-1,2,3,4-tetrahydro-quinazoline, exhibitanti-inflammatory effects.

Cross-references to related applications This is a continuation-in-partof application Ser. No. 509,613, filed Nov. 24, 1965 and now abandoned.

Summary of the invention The present invention concerns and has for itsobject the provision of newl-aryl-4-imino-1,2,3,4-tetrahydroquinazolines, more particularly thoseof Formula I, in which Phstands for a 1,2-phenylene radical, R for anaromatic radical, R for an aliphatic or aromatic radical, R for hydrogenor an aliphatic radical, one of R and R for hydrogen, an aliphaticradical or aromatic radical and the other for hydrogen or an aliphaticradical, N- oxides, quaternaries and salts thereof, correspondingpharmaceutical compositions as well as methods for the preparation ofthe new compounds. Said compositions are primarily useful asanti-inflammatory agents, preferably for oral application in place ofcorticosteroids, in the treatment of tissue inflammations, such asarthritic and similar conditions, but also as diuretic agents for therelief of edema and the adjunctive management of hypertension.

Description of the preferred embodiments hydroxy, for example halogeno,such as fluoro, chloro or bromo, trifiuoromethyl, nitro, amino, forexample dilower alkylamino, such as dimethylamino or diethylamino.Preferred 1,2-phenylene radicals Ph are 1,2-phenylene',

3,403,152 Patented Sept. 24, 1968 (lower alky1)-1,2-phenylene, (loweralkoxy)-1,2-phenylene, (lower alkyl-mercapto)-1,2-phenylene, (halogeno)-1,2-phenylene, (trifiuoro-methyl)-1,2-phenylene, (nitro)- 1,2-phenyleneand (di-lower alkyl-amino)-1,2-phenylene.

An aromatic radical R R R and or R particularly stands for monoorbicyclic carbocyclic aryl, i.e. phenyl, 1- or Z-naphthyl, or monocyclicheterocyclic aryl, such as furyl, thienyl or pyridyl. Said aryl groupsare unsubstituted or contain one or more than one of the same ordifferent substituents attached to any position available forsubstitution, for example those mentioned for Ph. They stand primarilyfor phenyl, (lower alkyl)-phenyl, (lower alkoxy) -phenyl, (loweralkylmercapto)-phenyl, (halogeno)-phenyl, (trifluoromethy1)-phenyl,(nitro)-phenyl or (di-lower alkylamino)-phenyl.

An aliphatic radical R R R and/or R represents especially lower alkyl,e.g. methyl, ethyl, nor i-propyl, -butyl, -pentyl, -hexyl or -heptyl. Itcan also stand for lower alkenyl, such as allyl or methallyl, 3 to 8ring-membered cyclo-alkyl or cycloalkyl-lower alkyl, especially suchhaving fiveto seven ring-carbon atoms, such as cyclopropyl, cyclopentyl,cyclohexyl, cycloheptyl or cyclooctyl; cyclopropylmethyl,cyclopentylmethyl, 2-cyclopentylethyl, cyclohexylmethyl,l-cyclohexylethyl or cycloheptylmethyl, as well as monocycliccarbocyclic aryl-lower alkyl, such as benzyl, 1- or 2-phenylethyl. Theseradicals may contain additional substituents, especially in the aromaticportion, such as those mentioned for Ph, as well as 0x0 or thiono in thealiphatic portion. They also may be interrupted by hetero atoms,preferably by one oxygen, sulfur and/ or nitrogen atom. Such radicalsare, for example lower alkoxy-lower alkyl, such as methoxymethyl,ethoxymethyl, n-propoxymethyl, 1- or 2-methoxy-, ethoxy ori-propoxyethyl, 1-, 2- or 3-methoxy-, ethoxyor npropoxy-propyl or4-tert. butoxy-butyl, the corresponding phenoxylower alkyl and loweralkylmercapto-lower alkyl groups, m0noor di-lower alkylamino-loweralkyl, lower alkyleneiminon-propoxymethyl, 1- or 2-methoxy-, ethoxy ori-propoxylower alkyl, aza, oxaor thia-alkyleneimino-lower alkyl orN-lower alkylor phenyl-aza-alkyleneimino-lower alkyl groups with 4 to 6ring-carbon atoms and in which radicals the heteroatoms are separated byat least two carbon atoms, such as 2-methylamino-, Z-dimethylaminoor 2-diethylamino ethyl, 3-dimethylaminoor '3-diethylaminopropyl,2-pyrrolidino-ethyl, 3-piperidino-propyl, 2-piperaZino-ethyl, 2 (4methyl-piperazino)-ethyl, 3 (4 ethylpiperazino)-propyl,2-(4-phenyl-piperazino)-ethyl, 2- imorpholino-ethyl or3-thiamorpholino-propyl.

The quaternaries are particularly those containing additional loweralkyl or aralkyl groups, such as those mentioned above, quaternizing atleast one tertiary nitrogen atom present.

The compounds of this invention have useful pharmacological properties.Apart from some diuretic effects, they exhibit primarilyanti-inflammatory activity, as can be demonstrated in animal tests usingmammals, for example, rats as test objects. Besides theirabove-mentioned utility, the compounds of the invention are alsovaluable intermediates in the preparation of other useful products,particularly of pharmacologically active compounds. Thus, thecorresponding 1-aryl-4-imino-1,4-dihydroquinazolines, disclosed incopending application Ser. No. 488,264, filed Sept. 17, 1965, areobtained from the compounds of this invention by dehydrogenation.

Particularly useful are compounds of the Formula I in which Ph standsfor 1,2-phenylene, (lower alkyl)-1,2-phenylene, (lower'alkoxy)-l,2-phenylene or (halogeno)- 1,2-phenylene, each of R and R forphenyl, (lower alkyl)- phenyl, (lower alkoxy)-phenyl or(halogeno)-phenyl, R also for lower alkyl, R for hydrogen or lower alkyland one of R and R for hydrogen and the other for lower alkyl, 3 to 8ring-membered cycloalkyl, lower alkoxylower alkyl, monoor di-loweralkylamino lower alkyl, alkyleneimino-lower alkyl in which alkylene hasfrom four to six carbon atoms, or azaor thiaalkylene iminolower alkyl inwhich the ring has from four to six carbon atoms and in which radicalsthe heteroatoms are separated from each other by at least two carbonatoms, and acid addition salts thereof.

Especially mentioned are those compounds of the Formula I in which Phstands for 1,2-phnylene, R for phenyl, 4-methoxy-phenyl, 4-fluoro-phenyland 4-chlorophenyl, R for phenyl, each of R and R for hydrogen and R forlower alkyl, and therapeutically acceptable acid addition salts thereof.

The compounds of Formula I, in which Ph stands for 1,2-phenylene, R for4-fluoro-phenyl, R for phenyl, each of R and R for hydrogen and R forhydrogen, methyl, ethyl, nor i-propyl, n-, ior sec. butyl which, whengiven orally to rats at doses between about 3 and 25 mg./kg./ day,preferably between about 5 and 15 mg./kg./day, show outstandinganti-inflammatory effects according to the granulama pouch orcarrageenin paw test.

The compounds of this invention are prepared according to known methods.For example, the process for their preparation consists in (a) reducinga l-aryl-4-amino-1,4-dihydro-quinazoline, more particularly a compoundof the Formula II (b) condensing a 2-arylamino-benzamidine with analdehyde or ketone, more particularly compounds of the Formulae III andIV Ph NH-lh x0 lTIII (III) (IV) in which X stands for oxygen or sulfur,or acetals or ketals of IV, or

(c) reacting a 1-aryl-4-alkoxyor alkylmercapto-1,2- dihydroquinazo-linewith ammonia or a primary amine, more particularly compounds of theFormulae V and VI in which R stands for lower alkyl and, if desired,converting any compound obtained into another disclosed compound.

In the reduction according to (a) either catalytically activated ornascent hydrogen alone, for example hydrogen in the presence of nickel,platinum or palladium catalysts, or electrolytically generated hydrogen,or reducing agents may be used, for example complex light metal hy- 4drides, such as alkali metal aluminum or borohydrides, e.g. lithiumaluminum hydride or sodium borohydride.

In the condensation according to (b) any water formed may either bedistilled off aceotropically or absorbed by a condensing agent, such asa carbodiimid.

The compounds obtained according to said process may be converted intoother disclosed compounds by methods in themselves known. Thus, forexample, into any primary, secondary or tertiary amino nitrogen atom,for example into compounds in wihch R and/or R stands for hydrogen, a,substituent may be introduced, if necessary after conversion of thecompound obtained into a metal, e.g. alkali metal, derivative thereof.This can be done, for example, by reaction with a reactive ester of anappropriate alcohol, for example, that of a hydrohalic, e.g.hydrochloric, hydrobromic or hydriodic acid, or a sulfonic acid, such asa lower alkane or benzene sulfonic acid, e.g. methane, ethane orp-toluene sulfonic acid, or an aryl diazonium salt, whereby highersubstituted amines or quartcrnaries are obtained, or by reductivealkylation, i.e. reaction with an appropriate oxo compound andsubsequent reduction, or by oxidation, for example With hydrogenperoxide, a percarboxylic or sulfonic acid, e.g. peracetic, perbenzoic,monoperphthalic or p-toluene persulfonic acid, in order to obtain theN-oxides. In compounds, amino-subst-ituted by radicals which can beeliminated, for example, amino-substituted by a-arylalkyl, e.g. benzyl,or phthaloyl radicals, the said radicals can be split off in the usualmanner by hydrogenolysis or hydrazinolysis.

The above-mentioned reactions are carried out according to standardmethods, in the presence or absence of diluents, preferably such as areinert to the reagents and are solvents thereof, of catalysts, condensingagents and/ or inert atmospheres, at low temperatures, room temperatureor elevated temperatures, at atmospheric or superatmospheric pressure.Condensing agents are especially used in the reaction with said reactiveesters of an alcohol in order to eliminate the acid formed. They arebasic agents, for example, alkali or alkaline earth metal carbonates orlower alkoxides, or more especially, organic bases such as pyridine orcollidine, but particularly aliphatic tertiary amines, such as atri-lower alkylamine, e.gtriethylamine.

The compounds of the invention are obtained in th free form or in theform of their salts, depending on the conditions under which the processis carried out; the salts are also included in the present invention.Salts that are obtained can be converted into the free bases in knownmanner, for example, with alkalis or ion exchangers. Free bases that areobtained can be converted into salts by reaction with inorganic ororganic acids, especially those that are suitable for the formation oftherapeutically useful salts. Such acids are, for example, hydrohalicacids, eg, hydrochloric or hydrobromic acid, sulfuric, phosphoric,nitric or perchloric acid, aliphatic, alicyclic, araliphatic, aromatic,or heterocyclic carboxylic or sulfonic acids, for example, formic,acetic, propionic, succinic, glycollic, lactic, malic, tartaric, citric,ascrobic, maleic, hydroxymaleic, pyroracemic, phenylacetic, benzoic,aminobenzoic, anthranilic, hydroxybenzoic, salicylic, aminosalicylic,embonic, nicotinic, methanesulfonic, ethanesulfonic,hydroxyethanesulfonic, ethylenesulfonic, halogenbenzenesulfonic,toluenesulfonic, naphthalenesulfonic and sulfanil-ic acid; methionine,tryptophan, lysine and arginine.

These or other salts, for example, the picrates, can also be used forpurification of the bases obtained; the bases are converted into salts,the salts are separated and the bases are liberated from the salts. Inview of the close relationship between the free compounds and thecompounds in the form of their salts, whenever a free base is referredto in this context, a corresponding salt is also intended, provided suchis possible or appropriate under the circumstances.

ful substances.

"invention and are-not to The invention further includes any variant'ofthe present process, in which an intermediate product obtainable at anystage of the process is used as starting material and any-remainingsteps are-carried out, or the process is discontinued at any stagethereof, or in which the starting materials; are formed under thereaction conditions, or in which the reaction components ar used in theform of their salts. Mainly, those starting materials should be used inthe reactions of the invention that lead to the formation of ;thosecompounds indicated above as being specially valuable.

The starting material used in reaction ('a) (which is the preferredmethod for the preparation of the new compounds) bis disclosed in theabove-mentioned copending application Ser. No. 488,264; it is preferablyused in the form of the free base. The-benzamidines used in reaction (b)can be obtainedfrom corresponding benzo-nitriles by reaction'withammonia, amines or metal amides, e.g. aminomagnesium halides or sodiumamides, or-- by condensation of corresponding anthranilic acid amideswith amines, preferably in the presence of phosphorus trichloride oroxychloride. The 1,2-dihydro-quinazolines used as starting material inreaction (c) may be prepared analogous to the reaction (b) using insteadof the amidines corresponding irnido esters, or by reduction ofcorresponding quaternary 1-aryl-4-alkoxyor alkylmercapto-quinazoliniumsalts 'also disclosed in the a-b'ovewmentioned co-pending application.

The compounds of this inventionare useful in the form of compositions;for enteral, parenteral or topical administration, which contain apharmacologically effective amount of the compounds of this invention inadmixture with apharmaceutically acceptable, organic or inorganic solidor liquid carrier, which usually represents the major portion of thepharmaceutical composition. For making up the latter, there are employedcarrier materials suitable, for the preparation of pharmaceuticalcompositions,-such as water, gelatine, sugars, e.g. lactose, glucose orsucrose, starches, e.g. corn starch, wheat starch or rise starch,stearic acid or salts thereof, e.g. calcium or magnesium stearate,talcrvegetable oils, alcohol, e.g. ethanol, benzyl alcohol or cetylalcohol, petrolatnm, gums, acacia, propylene glycol, polyalkyleneglycols or any other known carrier for pharmaceutical compositions. Thepharmaceutical preparations may be in-solid form-,ieglcapsule's, tabletsor dragees, in liquid form, e.g. solutions or suspensions, or in.the-form of emulsions, e.g. salves or creams; If desired, they maycontainqauxiliary.substanees, such as preserving, stabilizing, wettingemulsifying, or coloringagents, salts for varying the osmotic pressureor buffers. The above preparations are prepared according to standardmethods used for the manufacture'of pharmaceutical-1y acceptable compolsit'ions which containabout 0.1 to 75%, more particularly 1 to 50% of theactive ingredient. They ma also contain, in combination, otherpharmacologically use- The following examples are intended to illustratethe grade and all parts wherever ,given are parts by weight.

' ,,.-Example 1 hydro-quinazolihe in 255ml. absolute ethanol is addedand the mixture is hydrogenated under atmospheric pressure and:temperature until 25.1 m1. hydrogen have been absorbed. T he: mixture isfiltered, the filtrate evaporated 'unde'r' reduced pressure and theresidue dissolved in ml;- dimethylf'ormamide: Through the solutionmethylamine is bubbled-through for '3 minutes, excess water is added,the precipitate formed filtered off and recrystallized from diethylether to yield the 1-(4-fluoro-phenyl)- beconstrued' as being limit-a-'tions thereom-Temperatures are given in degrees centi- 2 phenyl 4methylimino,- l,2,3,4 tetrahydro quin- 'azolin'e of the formula v N-OH3Example 2 To the pre-reduced suspension of 0.1 g. platinum oxide in 10ml. anhydrous ethanol, the solution of 1 g. 1-(4- fluoro phenyl) 2phenyl 4 n propylimino 1,4- dihydro-qninazoline in 170 m1. anhydrousethanol is added and the mixture is hydrogenated under atmosphericpressure and temperature until 90.2 ml. hydrogen have been absorbed. Itis then filtered, evaporated in vacuo and the residue recrystallizedfrom diethyl ether to yield the 1 (4 fiuoro phenyl) 2 phenyl 4 npropylimino -1,2,3,4 tetrahydro quinazoline of the formula N-CHg-CHg-CHg\III CeHs melting at 171 to 173.

Example 3 4,5 In the manner described in Example 2, the followingcompounds are prepared from equivalent amounts of the correspondingstarting material, having the formulae NRs a A n N H2 N I Pt C H 5 I 5 51 (VII) Rs MP. of Recrystallized from- VII (de CiHs 147-148 Diethylether.

.ficetflne-hexane. 4 9.- 1 iet y etherentane. 1-C4H9... 137-138 Hexane.p

sec. CLHD 78-84 Aqueous methanol.

170-175 Diethyl ether.

-F 87-90 Diethyl ether-pentane.

A representative example for the preparation of the starting material isthe following:

To the mixture of 33.3 g. 4-fluoro-aniline and ml. pyridine, 42.1 g.benzoylchloride are added slowly while cooling and stirring. Hereuponthe reaction mixture is poured into 600 ml. water, the precipitateformed filtered off, washed with water and recrystallized from ethanolto yield the N-(4-fluoro-phenyl)-benzamide melting, afterrecrystallization from ethanol, at 183-187.

The mixture of 46.0 g. thereof and 100 ml. thionychloride is refluxedfor 3 hours and then evaporated. The residue is distilled and thefraction boiling at 180/ 20 mm. Hg collected. It represents theN-(4fluoro-phenyl)-benzimidchloride.

The solution of 4.66 g. thereof in 25 ml. diethyl ether is added rapidlyto the mixture prepared from the solution of 1.35 g. sodium methoxide in50 ml. anhydrous ethanol to which 4.56 g. methyl salicylate have beenadded rapidly while stirring. The mixture is allowed to stand at roomtemperature for 30 minutes and is evaporated in vacuo. The residue istriturated with water, filtered off and recrystallized from ethanol toyield the 2-carbomethoxy phenyl N (4 fluoro-phenyl)-benzimidoate meltingat l26l30.

85.0 g. thereof are heated to 275 for minutes. After cooling the residueis triturated with diethyl ether, filtered 01f andrecrystallized frommethanol to yield the methyl N-benzoyl-N-(4-fluoro-phenyl)-anthranilatemelting at 110-116".

To the solution of 34.9 g. thereof in 200 ml. ethanol and 110 ml. waterthe mixture of 5.4 g. sodium methoxide, 100 ml. ethanol and 20 ml. wateris added. The mixture is refluxed for 1% hours, concentrated and theaqueous solution acidified with concentrated hydrochloric acid. It isextracted with methylene chloride, the extract evapo' rated, the residuetaken up in aqueous sodium bicarbonate, the solution acidified withhydrochloric acid, the precipitate formed filtered ofl, dissolved inmethylene chloride, the solution dried and diluted with hexane. Theprecipitate formed is filtered off and recrystallized from diethyl etherto yield the N-benzoyl-N-(4-fluoro-phenyl)-anthranilic acid melting at176 to 178.

The mixture of 20.0 g. thereof and 100 ml. phosphorus oxychloride isrefluxed for 19 hours and then evaporated. The residue is taken up inabout 200 ml. methylene chloride and the solution of the resulting acidchloride treated for 1 hour with ammonia until it becomes basic. It iswashed with water, dried, concentrated, the concentrate diluted withhexane, the precipitate formed, filtered off, and recrystallized fromacetone-hexane to yield the 1-(4-fluoro-phenyl)-2-phenyl-3,4-dihydro-4-quinazolone melting at 289290.

The mixture of 10.5 g. thereof, 8.9 g. phosphorus pentasulfide and 150ml. xylene is refluxed to 2 hours while stirring. After cooling 60 ml.of 10% aqueous sodium hydroxide are added, the precipitate formedfiltered 01f, washed with hot ethanol and recrystallized with acetone,While using charcoal for decolorization, to yield the 1-(4-fluoro-phenyl)-2-phenyl-1,4-dihydroquinazolin 4 thione melting at293-296.

The mixture of 8.75 g. thereof and ml. methyliodide is refluxed for 1%hours. The solid is filtered off and recrystallized from acetone toyield the 1-(4-fluoro-phenyl)- 2-phenyl-4-methylmercapto-quinazoliniumiodide melting at 270-290 with decomposition.

To the solution of 2.0 g. thereof in 20 ml. dimethylformamide, 0.75 g.n-propylamine are added dropwise while stirring. After standing for 15minutes at room temperature, water is added, the precipitate formedfiltered off and recrystallized from acetone to yield the desired1-(4-fluoro-phenyl)-2-phenyl-4-n-propylimino 1,4 dihydro-quinazolinemelting at 234 to 235".

'Example 4 In the manner shown in the previous examples, the followingcompounds are prepared by using the equivalent amounts of thecorresponding starting materials:

4- Z-methyl-propylimino) l- (4-fiuoro-phenyl-2-phenyll,2,3,4-tetrahydro-quinazoline,

8 4-r1-pentyliminol-(4-fluoro phenyl) 2-p henyl-1,2,3,4-tetrahydrmquinazoline, v4-(4-fluorophenylimino)-l-(4-fluoro-phenyl)-2-phenyl-1,2,3,4-tetrahydro-quinazoline, j 4- (4-fluorophenylimino 1 -(4-flu'oro-phenyl )"-2-phei1yl l,2,3,4-tetrahydro quinazoline,4-cyclopropylimino-1 (4-fiuoro-phenyl)-2-phenyl- 1,2,3,4 tetrahydroquinazoline, 5 i 4-cyclopropylmethylimino-1- (4-fluoro-phenyl)-2-phenyl- 1,2,3,4-tetrahydroquinazoline, I 4-(2-butylimino)-1,2,diphenyl-1,2,3,4-tetrahydro-- quinazoline,4-cyclopropylimino-1,2,-diphenyl-l,2;3,4-tetrahydroquinazoline, I i4-(4-fluorobenzylimino) 1,2-di-phenyl-l,2,3,4-tetrahydroquinazoline, i

4- 2-butylimino 1 (4-chloro-phenyl) -2-phenyl-' 1,2,3 ,4-

tetrahydro-quinazoline, I Y I4-(Z-methyl-propyl)-1-(4-chloro-pl1enyl)-2-phenyl-1,2,3,4-tetrahydro-quinazoline,4-(2-ethylamino-ethylimino)-1-phenyl-2-methyl-1,2,3,4-tetrahydro-quinazoline, 4-(2-pyrrolidino-ethylimino) -1-(4-methyl-phenyl) -2- ethyl-1,2,3,4-tetrahydro-quinazoline, 4-(2-piperazino-ethylimino) -1- (3 trifluoromethyl-phenyl)Z-benzyl-l,2,3,4-tetrahydro-quinazoline,4-(2-morpholino-ethylimino)-1,2-diphenyl-6-meth0xyl,2,3,4-tetrahydro-quinazoline,4-(Z-thiamorpholino-ethylimino)-1,2-dipl1enyl 6-rnethyl1,2,3,4-tetrahydro-quinazoline,4-cyclopentyl-imino-6-chloro-l,2-diphenyl-1,2,3,4

tetrahydro-quinazoline, 4- 2-ethoxy-ethylimino 1-( 3 ,4-dichloro-phenyl)-2- (4- methyl-phenyl)-l,2,3,4-tetrahydro-quinazoline, 4-3-methylmercapto-propylimino 1- (4-bromo-phenyl)2-isopropyl-1,2,3,4-tetrahydro-quinazoline, 4- (Z-phenoxy-ethylimino-1-phenyl-2-(3-nitro-phenyl) 1,2,3,4-tetrahydro-quinazoline,4-cyclopropylmethylimino-1-phenyl-2-(4-bromophenyl)-1,2,3,4-tetrahydro-quinazoline,4-benzylimino-l-phenyl-2-(4-methyl-phenyl)-1,2,3,4-

tetrahydro-quinazoline, 4-(2-cyclopntyl-ethylimino) -1-(2-naphthyl) -2-(4- methoxy-phenyl 1,2, 3 ,4-tetrahydro-quinazoline,4-n-hexylimino-l-phenyl-Z-(4-methylmercapto-phenyl)- 1,2,3,4-tetrahydroquinazoline,4-imino-1-(4-chloro-phenyl)-2-phenyl-1,2,3,4-tetrahydroquinazoline.

Example 5 Preparation of 10,000 tablets, each containing 10 of the drugsubstance- Formula: i Grams 4 n propylimino 1-(4-fluoro-phenyl)-2-phenyl-1,2,3,4-tetrahydro-quinazoline 100.00 Lactose 1,157.00 Talcumpowder 75.00 Magnesium stearate .18.00 Corn starch, anhydrous .00Polyethylene glycol. 6000 m.w. M 7 5.00 Purified water q. s.

Procedure The drug substance, lactose; talcum, magnesium stearate andhalf of the starch are passed througha screen with 1 mm. openings andmixed thoroughly. .The:remair1- ing 37.5 g. of the starch are suspendedin 37.5;ml. w ate r, 112.5 ml. boiling water, are added while stirring,followed by the mixture of the polyethylene-glycol. and 37.5 ml. water.With the resulting paste. the mixed powder is gran ulated, using more,water if requiredflhe granulate is dried overnight at 35-40";brokerrthrough ascreen with 4 mm. openings and compressed into tabletsusing 6.4 mm. concave punches, uppers bisected.- 1 n In the aboveformula the drug substance can hereplaced by the same amount of4-ethylimino-, 4-i-propyliminoor 4 nbutylimino-1-(4-fluoro-p-henyl)-2-phenyl-1,2,3,4-tetrahydro-quinazoline.

I claim: 1. A member selected from the group consisting of the compoundhaving the formula Iii-R in which Ph is a member selected from the groupconsisting of 1,2-phenylene, (lower alkyl)-1,2-phenylene, (lower alkoxy-1,2-phenylene, (lower alkylmercapto -1,2-phenylene,(halogeno)-l,2-phenylene, (trifluoromethyl)-1,2- phenylene,(nitro)-l,2-phenylene, and (di-lower alkylamino)-l,2-phenylene, R is amember selected from the group consisting of phenyl, (loweralkyl)-phenyl, (lower alkoxy) phenyl, (lower alkylmercapto) phenyl,(halogeno)-phenyl, '(trifluoromethyD-phenyl, (nitro)-lphenyl and(di-lower alkylamino)-phenyl, R is a member selected from the groupconsisting of R lower alkyl, lower alkenyl, 3 to 8 ring-memberedcycloalkyl and cycloalkyllower alkyl, phenyl-lower alkyl, loweralkoxy-lower alkyl, lower alkylmercapto-lower alkyl, phenoxy-loweralkyl, lower alkylamino-lower alkyl, di-lower alkylamino-lower alkyl,lower alkyleneimino-lower alkyl, 6 to 8 ring-memberedazaalkyleneimino-lower alkyl, oxaalkyleneiminolower alkyl andthiaalkyleneimino-lower alkyl in which the heteroatoms are separated byat least two carbon atoms, R is a member selected from the groupconsisting of hydrogen and lower alkyl, one of R and R is a memberselected from the group consisting of hydrogen and R and the other is amember selected from the group consisting of hydrogen, lower alkyl,lower alkenyl, 3 to 8 ring-membered cycloalkyl and cycloalkyl-loweralkyl, phenyl-lower alkyl, lower alkoxy-lower alkyl, loweralkylmercapto-lower alkyl, phenoxy-lower alkyl, lower alkylamino-loweralkyl, di-lower alkylamino-lower alkyl, lower alkyleneimino-lower alkyl,6 to 8 ring-membered azaalkyleneimino-lower alkyl,oxaalkyleneimino-lower alkyl and thiaalkyleneimino-lower alkyl in whichthe heteroatoms are separated 'by at least two carbon atoms, theN-oxides, therapeutically acceptable lower alkyl and phenyl-lower alkylquaternaries, and therapeutically acceptable acid addition saltsthereof.

2. A compound as claimed in claim 1 and having the formula N-Ra in whichPh is a member selected from the group consisting of 1,2 phenylene,(lower alkyl)-1,2-phenylene, (lower alkoxy)-l,2-phenylene and(halogeno)-1,2-phenylene, R

is a member selected from the group consisting of phenyl, (loweralkyl)-phenyl, (lower alkoxy)-phenyl and (halogeno)-phenyl, R is amember selected from the group consisting of lower alkyl, phenyl, (loweralkyl)-phenyl, (lower alkoxy) phenyl and (halogeno)-phenyl, R is amember selected from the group consisting of hydrogen and lower alkylone of R and R is a member selected from the group consisting ofhydrogen and lower alkyl and the other is a member selected from thegroup consisting of hydrogen, lower alkyl, 3 to 8 ring-memberedcycloalkyl, lower alkoxy-lower alkyl, lower alkylaminolower alkyl,di-lower alkylamino-lower alkyl, 5 to 7 ringmem'beredalkyleneimino-lower alkyl, 6 to 8 ring-membered azaalkyleneimino-loweralkyl, oxaalkyleneiminolower alkyl and thiaalkyleneimino-lower alkyl inwhich the heteroatoms are separated by at least two carbon atoms, andtherapeutically acceptable acid addition salts thereof.

3. A compound as claimed in claim 1 and having the formula in which R isa member selected from the group consisting of phenyl, 4-methoxy-phenyl,4-fiuoro-phenyl and 4- chloro-phenyl and R is lower alkyl andtherapeutically acceptable acid addition salts thereof.

4. A- compound as claimed in claim 1 and having the formula in which Ris a member selected from the group consisting of hydrogen, methyl,ethyl, n-propyl, i-propyl, n-butyl and sec. butyl and therapeuticallyacceptable acid addition salts thereof.

5. A compound as claimed in claim 1 and being the 4- (4 fluorophenylimino) 1-(4-fiuoro-phenyl)-2-phenyl-1,2,3,4-tetrahydro-quinazoline.

References Cited UNITED STATES PATENTS 3,340,260 9/1967 Blatter 260256.4

NICHOLAS S. RIZZO, Primary Examiner. R. J. GALLAGHER, AssistantExaminer.

